ATP-sensitive potassium (KATP) channels play a critical role in many cellular stress responses by linking cellular metabolism and membrane potential. KATP channels are also the target of sulfonylurea drugs used to treat diabetes. The sulfonylurea receptor 2 (SUR2) is the regulatory subunit of cardiac KATP channel and directly binds to ADP. Therefore, the energy state of the cell determines channel opening. KATP channels are also present in mitochondria, but the molecular components of the mitochondrial channels are less clear. The major goal of the proposal is to determine the role of SUR2 in cardiac KATP cannels. Our laboratory's previous results show that mice lacking exons 14 to 18 (Ex14/18) of the SUR2 gene display vasospasm, arrhythmia, and sudden cardiac death. Surprisingly, the myocardial ischemic stress response was not attenuated in Ex14/18 mice. The discovery of shorter proteins related to SUR2 and produced from the same gene has suggested that these SUR2 short forms may confer ischemic resistance independent of canonical KATP channels. These SUR2 short forms were unperturbed in the Ex14/18 mouse. To explore this hypothesis, a new mouse was generated where exon 5 was deleted from the SUR gene. Exon 5 encodes a region critical for the translocation of both full and short SUR2 isoforms from the endoplasmic reticulum. While Ex14/18 mice survive until adulthood, Ex5 mice exhibit progressive cardiac dysfunction and die within 10 days of birth. I hypothesize that the Ex5 deletion affects both full length and short SUR2 forms. In AIM 1, I will study the developmental expression patterns of SUR2 short forms in normal, Ex14/18, and Ex5 hearts. In AIM 2, I will determine how of the SUR2 short forms contribute the KATP function by examining how SUR2 and the KATP potassium channel subunit, Kir6.2 interact and localize. In AIM 3, I will determine whether cardiac-specific expression of full length SUR2 is able to rescue the severe phenotype of Ex5 mice. The work from this proposal will shed light on the role of KATP channels in development and cardiac stress.